PROCESS FOR PREPARING SUBSTITUTED 5-AMINO-PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO[1,5-c]PYRIMIDINES

ABSTRACT

A process for preparing substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compounds having an aminoalkyl substituent at the 7-position is disclosed, wherein the pyrimidine ring is cyclized using a cyanating agent.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. patent applicationSer. No. 11/788,682, filed Apr. 20, 2007, which application isincorporated herein in its entirety by reference as if fully set forth,and which application in turn is a continuing application based on andclaiming the priority of U.S. patent application Ser. No. 10/973,631,filed Oct. 26, 2004, which application in turn is based on and claimsthe priority of U.S. Provisional Application Ser. No. 60/515,051, filedOct. 28, 2003, the disclosure of each of which applications are alsoincorporated herein by reference in their entirety as if fully setforth.

FIELD OF THE INVENTION

The present invention relates to a process for preparing substituted5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compoundshaving an aminoalkyl substituent at the 7-position.

BACKGROUND

Substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidinecompounds disclosed in WO 01/92264 are useful as A_(2a), receptorantagonists in the treatment of central nervous system diseases, inparticular Parkinson's disease.

WO 01/92264 discloses processes for preparing5-amino-2-substituted-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidinescomprising dehydrative rearrangement of hydrazines. Baraldi et al, J.Med. Chem., 41, (1998), p. 2126-2133 disclose formation of a5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine having aphenylalkyl substituent at the 7-position, wherein the reactioncomprises reacting a phenylalkyl-substituted hydrazide with(ethoxymethylene)malonitrile to form a substituted pyrazole. Baraldi etal, J. Med. Chem., 39, (1996), p. 1164-1171 disclose formation of a7-substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidineby reaction of an alkylated pyrazole with (ethoxymethylene)malonitrile.Both Baraldi et al process use NH₂CN to accomplish the final ringclosure.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing compoundshaving the structural formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein

R is R¹-furanyl, R¹-thienyl, R¹-pyridyl, R¹-pyridyl N-oxide,R¹-oxazolyl, R¹⁰-phenyl, R¹-pyrrolyl or cycloalkenyl;

X is C₂-C₆ alkylene;

Y is —N(R²)CH₂CH₂N(R³)—, —OCH₂CH₂N(R²)—, —(CH₂)₂—NH—, or

and

Z is R⁵-phenyl, R⁵-phenylalkyl, R⁵-heteroaryl, diphenylmethyl, R⁶—C(O)—

R⁶—SO₂—,

or phenyl-CH(OH)—; or when Q is

Z is also phenylamino or pyridylamino;or

Z and Y together are

R¹ is 1 to 3 substituents independently selected from hydrogen, alkyl,—CF₃, halogen, —NO₂, —NR¹²R¹³, alkoxy, alkylthio, alkylsulfinyl, andalkylsulfonyl;

R² and R³ are independently selected from the group consisting ofhydrogen and alkyl;

m and n are independently 2-3;

Q is

R⁴ is 1-2 substituents independently selected from the group consistingof hydrogen and alkyl, or two R⁴ substituents on the same carbon canform ═O;

R⁵ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN,dialkyl-amino, —CF₃, —OCF₃, acetyl, —NO₂, hydroxyalkoxy, alkoxyalkoxy,dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy,alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy,morpholinyl, alkyl-SO₂—, alkyl-SO₂-alkoxy, tetrahydropyranyloxy,alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, —SO₂NH₂,or phenoxy; or adjacent R⁵ substituents together are —O—CH₂—O—,—O—CH₂CH₂—O—, —O—CF₂—O— or —O—CF₂CF₂—O— and form a ring with the carbonatoms to which they are attached;

R⁶ is alkyl, R⁵-phenyl, R⁵-phenylalkyl, thienyl, pyridyl, cycloalkyl,alkyl-OC(O)—NH—(C₁-C₆)alkyl-, dialkyl-aminomethyl, or

R⁹ is 1-2 groups independently selected from hydrogen, alkyl, hydroxy,alkoxy, halogen, —CF₃ and alkoxy-alkoxy;

R¹⁰ is 1 to 5 substituents independently selected from the groupconsisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, —NH₂,alkylamino, dialkylamino, —CF₃, —OCF₃ and —S(O)₀₋₂ alkyl;

R¹² is H or alkyl; and

R¹³ is alkyl-C(O)— or alkyl-SO₂—; comprising

-   -   a) reacting the hydroxyl group of a pyrazole of formula II

-   -   with an activating agent in the presence of a base to obtain a        compound of formula III

-   -   wherein L is a leaving group, and coupling the compound of        formula III with a compound of formula IV

Z-Y—H  IV

-   -   in the presence of a base to obtain a compound of formula V

-   -   b) treating the compound of formula V with trialkyl orthoformate        in the presence of a catalytic amount of acid to obtain a        compound of formula VI

-   -   wherein R⁷ is alkyl;    -   c) condensing the compound of formula VI with a hydrazide of        formula VII

H₂NHN—C(O)—R  VII

-   -   in the presence of an acid to obtain a compound of formula VIII

-   -   and hydrolyzing the compound of formula VIII to obtain a        compound of formula IX

-   -   d) cyclizing the compound of formula IX with a cyanating agent        selected from the group consisting of cyanates and cyanogen        halides in the presence of a base to obtain a compound of        formula I.

In particular, the invention relates to cyclizing a compound of formulaIX with a cyanating agent to obtain a compound of formula I.

DETAILED DESCRIPTION

Preferred compounds of formula I prepared by the claimed process arethose wherein R is R¹-furanyl, R¹-thienyl, R¹-pyrrolyl or R¹⁰-phenyl,more preferably R¹-furanyl. R¹ is preferably hydrogen or halogen.

Another group of preferred compounds is that wherein X is ethylene.

Y is preferably

wherein Q is

with Q preferably being nitrogen. Preferably, m and n are each 2, and R⁴is H.

A preferred definition for Z is R⁵-phenyl, R⁵-heteroaryl, R⁶—C(O)— orR⁶—SO₂—. R⁵ is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy oralkoxyalkoxy. R⁶ is preferably R⁵-phenyl. Especially preferred arecompounds wherein Z is R⁵-phenyl and R⁵ is one substituent selected fromthe group consisting of alkoxy and alkoxyalkoxy. A preferred alkoxygroup is methoxy, with alkoxyalkoxy being more preferred, e.g.,methoxyethoxy and ethoxyethoxy; methoxyethoxy is most preferred.

In step a, preferred embodiments of the process use a compound offormula IV-A:

In step b, the preferred trialkyl orthoformate is triethyl orthoformate.

Preferred embodiments of the process use 2-furoic hydrazide in step c(formula VII), thus preparing compounds of formula I wherein R is2-furyl.

Preferred reagents for the cyclization in step f are cyanates.

In a preferred aspect, the process of the invention comprises thepreparation of compounds of the formulas I-A to I-C:

In a most preferred aspect, the process of the invention comprises thepreparation of a compound of formula I-A comprising:

-   -   a) reacting the hydroxyl group of a pyrazole of formula II

-   -   with methanesulfonyl chloride in the presence of a base to        obtain a compound of formula IIIa

-   -   and coupling the compound of formula IIIa with a compound of        formula IVa

-   -   in the presence of a base to obtain a compound of formula Va

-   -   b) treating the compound of formula Va with trimethyl        orthoformate in the presence of a catalytic amount of an acid to        obtain a compound of formula VIa

-   -   c) condensing the compound of formula VIa with a hydrazide of        formula VIIa

-   -   in the presence of an acid to obtain a compound of formula VIIIa

-   -   and hydrolyzing the compound of formula VIIIa to obtain a        compound of formula IXa

-   -   d) cyclizing the compound of formula IXa with a cyanating agent        selected from the group consisting of cyanates and cyanogen        halides in the presence of a base.

Starting materials of formula II are known in the art (see, for example,Baraldi et al, J. Med. Chem., 39, (1996), p 1165).

In step a, the hydroxyl group on the compound of formula II is reactedwith an activating agent comprising a leaving group, L, wherein L is anoptionally substituted alkylsulfonyl- or arylsulfonyl-group. When L is asulfonyl group such as methanesulfonyl, trifluoromethanesulfonyl,ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl,p-bromobenzenesulfonyl or m-nitrobenzene-sulfonyl, typically theL-containing activating agent is an L-halide, e.g., methansulfonylchloride. A preferred leaving group is methanesulfonyl.

The reaction is carried out in a non-protic organic solvent such asCH₃CN at a temperature of about −20° C. to about 0° C., most preferablyat about 0° C. About 1-2, preferably about 1-1.5 equivalents ofactivating reagent are used, and about 1-2, preferably about 1-1.5equivalents of an organic base such as diisopropylethyl amine. Theactivated compound of formula III is not isolated.

The compound of formula III is coupled with an amine of formula IV. Thereaction is carried out in the presence of an inorganic base such asNaOH or K₂CO₃, at a temperature range of −50° C. to about 150° C.,preferably at about −20° C. to about 0° C., most preferably at about−10° C. About 1-2 equivalents of base are used.

In step b, the amino substituent on the compound of formula V isconverted to the imidate by treatment with 1-10 equivalents of atrialkyl orthoformate in a non-protic organic solvent such as toluene atreflux temperature in the presence of a catalytic amount of acid (e.g.,about 1 mol %). Any organic or inorganic acid can be used, but apreferred acid is p-toluenensulfonic acid. A preferred trialkylorthoformate is trimethyl orthoformate.

The imidate of formula VI is then condensed with a hydrazide of formulaVII in step c. The reaction is carried out in an organic solvent such astoluene at a temperature range of about −20° C. to about 110° C. in thepresence of 1-2 equivalents of an acid such as isobutyric acid.

The compound of formula VIII is then hydrolysed under acidic conditionsto form the ring-opened compound of formula IX. The acid can be amineral acid or an alkyl or aryl sulfonic acid; the concentration ofacid is not critical, but is preferably at 2-5%. The reaction is carriedout at temperature range of about room temperature to about 110° C.

In step d, the compound of formula IX is cyclized by treatment with acyanating agent selected from the group consisting of cyanates andcyanogen halides to obtain a compound of formula I. The reaction isconducted in an organic solvent such as CH₃CN or tetrahydrofuran (THF)at a ratio of 4-20 w/v, preferably about 5 w/v, optionally in thepresence of water (0 to 30% v/v, preferably about 10%). An inorganicbase (e.g, Na₂CO₃, NaHCO₃, KHCO₃, NaOH, KOH, K₃PO₄, K₂HPO₄, Na₃PO₄,Na₂HPO₄) or organic base (e.g., trialkylamine) is added a ratio of about0.2 to 0.5 equivalents. The reaction is carried out at a temperature ofabout 35° C. to reflux, preferably about 53° C. to about 58° C. 1-2equivalents of the cyanating agent are used, wherein the cyanating agentis a cyanate or a cyanogen halide. Cyanates (i.e., compounds of theformula Ar—OCN, wherein Ar is an optionally substituted aromatic moiety)are exemplified by substituted phenyl cyanates such as 2-methoxyphenylcyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol Acyanate. Cyanogen halides are exemplified by cyanogen bromide andcyanogen chloride. Cyanates are preferred, with 2-methoxyphenyl cyanatebeing most preferred. The reaction is quenched by the addition of anaqueous solution of an inorganic base (e.g., Na₂CO₃, NaHCO₃, KHCO₃,NaOH, KOH, K₃PO₄, K₂HPO₄, Na₃PO₄, Na₂HPO₄).

The present process provides an advantage over the procedures previouslyreported in the art. Known processes used highly toxic and corrosiveNH₂CN to cyclize the ring, while the present process uses a cyanatingagent such as a cyanate (e.g., 2-methoxyphenyl cyanate) or a cyanogenhalide (e.g., cyanogen bromide). Furthermore, the preferred cyanatingagents, cyanates, are preferable to the relatively more toxic cyanogenhalides. Also, the temperature range for conducting the second part ofstep a of this invention is about 150° C. lower than that used inliterature preparations. The present invention therefore, allows forlarge scale production and high yields using milder conditions.

As used herein, “alkyl” means an aliphatic hydrocarbon group which maybe straight or branched and comprising about 1 to about 6 carbon atomsin the chain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl, are attached to a linear alkyl chain. Alkylene,referring to a divalent alkyl group, similarly refers to straight orbranched chains.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described, unless otherwise noted. Non-limiting examples ofsuitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy and heptoxy. The bond to the parent moiety is through the etheroxygen.

“Cycloalkyl” means a non-aromatic ring system comprising about 3 toabout 6 carbon atoms. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl and cyclohexyl, and thelike. Cycloalkylene refers to a divalent cycloalkyl group. Cycloalkenylrefers to a C₄-C₆ cycloalkyl ring comprising one double bond.

“Heteroaryl” means a single ring, bicyclic or benzofused heteroaromaticgroup of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4heteroatoms independently selected from the group consisting of N, O andS, provided that the rings do not include adjacent oxygen and/or sulfuratoms. N-oxides of the ring nitrogens are also included. Examples ofsingle-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl,oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl,tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl,pyridazinyl and triazolyl. Examples of bicyclic heteroaryl groups arenaphthyridyl (e.g., 1, 5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl,pyridopyrimidinyl and 7-azaindolyl. Examples of benzofused heteroarylgroups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl(i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl andbenzofurazanyl. All positional isomers are contemplated, e.g.,2-pyridyl, 3-pyridyl and 4-pyridyl. R⁵-substituted heteroaryl refers tosuch groups wherein substitutable ring carbon atoms have a substituentas defined above.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio, ethylthio, and i-propylthio. The bond to the parentmoiety is through the sulfur.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. The bond to the parentmoiety is through the sulfonyl.

“Alkylsulfinyl” means an alkyl-S(O)— group. The bond to the parentmoiety is through the sulfinyl.

“Carbonyl” means a —C(O)— moiety, e.g., alkoxycarbonyl refers to analkoxy-C(O)— group (i.e., alkyl-O—C(O)—).

“Acetyl” means —C(O)CH₃.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

Certain compounds of the invention may exist in different stereoisomericforms (e.g., enantiomers, diastereoisomers and atropisomers). Theinvention contemplates all such stereoisomers both in pure form and inmixture, including racemic mixtures.

Certain compounds will be acidic in nature, e.g. those compounds whichpossess a carboxyl or phenolic hydroxyl group. These compounds may formpharmaceutically acceptable salts. Examples of such salts may includesodium, potassium, calcium, aluminum, gold and silver salts. Alsocontemplated are salts formed with pharmaceutically acceptable aminessuch as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine andthe like.

Certain basic compounds also form pharmaceutically acceptable salts,e.g., acid addition salts. For example, pyrido-nitrogen atoms may formsalts with strong acid, while compounds having basic substituents suchas amino groups also form salts with weaker acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those skilled in the art. The salts are prepared by contactingthe free base form with a sufficient amount of the desired acid toproduce a salt in the conventional manner. The free base forms may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwise equivalentto their respective free base forms for purposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Following are descriptions of the preparation of compound I-A using theclaimed process.

The following abbreviations are used in the specification and claims: Ms(methylsulfonyl); Me (methyl); Et (ethyl); LOD (loss on drying); DMAP(4-dimtheylamino-pyridine); and DMSO (dimethyl sulfoxide).

Example 1

Step a:

To a mixture of compound II (200.0 g, 1.0 eq.) and diisopropylethylamine (280 ml, 1.2 eq.) in CH₃CN (600 ml) at 0° C. was slowly addedCH₃SO₂Cl (112 ml, 1.1 eq.). After the addition was complete, NaOH (25%,250 ml) was added at 5° C. followed by a solution of compound IVa (34.2g, 1.1 eq.) in water (600 ml). The reaction mixture was refluxed for 6h, and then concentrated to a volume of 900 ml to remove CH₃CN. Water(1.2 l) was added to the reaction mixture and the batch was cooled to22° C. The batch was filtered and washed the wet cake with water (600ml), and dried in a vacuum at 65° C. for 24 h. A yellow product wasobtained (ca. 415 g). ¹HNMR (CDCl₃): 7.52 (s, 1H), 6.95 (s, 4H), 5.89(s, 2H), 4.18 (m, 2H), 4.06 (m, 2H), 3.78 (m, 2H), 3.47 (s, 3H), 3.11(m, 4H), 2.83 (m, 2H), 2.72 (m, 4H).

Step b:

A mixture of compound Va (150.0 g, 1.0 eq.), trimethyl orthoformate (120ml, 2.6 eq.) and a catalytic amount of p-toluenesulfonic acid in toluene(1.2 l) was heated to a temperature between 105 and 115° C. The reactionmixture was slowly concentrated to 520 ml. The reaction mixture was thencooled to 15 to 25° C. and heptane (1.6 l) was added to complete theprecipitation. The batch was filtered, washed with heptane and dried ina vacuum oven at 20 to 30° C. for about 24 h to a LOD<0.5%. A light grayproduct was obtained (ca. 160.8 g).

Mass spectrum: M+1=413. ¹HNMR (DMSO): 8.55 (s, 1H), 7.90 (s, 1H), 6.80(m, 4H), 4.15 (m, 2H), 4.00 (m, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 3.30(s, 3H), 2.94 (bs, 4H), 2.70 (bs, 2H), 2.55 (bs, 4H). ¹³CNMR (DMSO):162.5, 152.4, 150.4, 141.4, 117.6, 115.3, 114.8, 79.7, 70.9, 67.5, 58.5,56.9, 55.0, 53.0, 49.7, 45.3.

Alternate Step b:

A mixture of compound Va (300.0 g, 1.0 eq.), triethyl orthoformate (280ml, 2.6 eq.) and a catalytic amount of p-toluenesulfonic acid (3.0 g) intoluene (1.8 l) was heated to a temperature between 105 and 115° C. Thereaction mixture was slowly concentrated to 1000 ml. The reactionmixture was then cooled to 15 to 25° C. and heptane (2.1 l) was added tocomplete the precipitation. The batch was filtered, washed with heptaneand dried in a vacuum oven at 20 to 30° C. for about 24 h to a LOD<0.5%.A light gray product, VIb, was obtained (ca. 301.2 g).

Mass Spectrum: M+1=427. ¹HNMR (DMSO): 8.50 (S, 1H), 7.92 (S, 1H), 6.81(m, 4H), 4.35 (m, 2H), 4.10 (t, 2H), 3.99 (m 2H), 3.60 (m, 2H), 3.30 (s,3H), 2.90 (bs, 4H), 2.50 (m, 4H), 2.70 (t, 2H), 1.38 (t, 3H). ¹³CNMR(DMSO): 162.1, 152.4, 150.6, 145.8, 141.4, 117.6, 115.3, 114.9,79.770.9, 67.4, 64.1, 58.5, 56.9, 53.0, 49.7, 45.4, 14.2.

Steps c:

Compound VIa (100 g, 1.0 eq.), compound VIIa (2-furoic hydrazide) (28.8g, 0.97 eq.), toluene (400 ml), and isobutyric acid (23 ml, 1.0 eq.)were combined and the reaction mixture was heated to 50° C. and stirredfor over 4 h. The reaction mixture was distilled off to about 300 ml at50° C. The reaction mixture was heated to 110° C., azeotropicdistillation was done to remove the water generated during the reaction,and then the mixture was stirred at 110-115° C. for over 4 h. Aftercooling to 25° C., the reaction mixture was added to 4.1% HCl solution(450 ml) and heated to reflux. The reaction mixture was stirred atreflux for over 2 h, and then cooled to 25° C. The reaction mixture wassettled and the aqueous layer was separated from the organic layer. Theaqueous layer was heated to 50° C. and the pH adjusted to between 1.8and 2.8. After pH adjustment, the aqueous layer was stirred at 50° C.for 30 min, and then slowly cooled to 0° C. for over 2 h. The aqueouslayer was stirred at 0° C. for 1 h to complete the precipitation. Thesolid was filtered and washed with water (250 ml). The product was driedin a vacuum oven at 75-80° C. The product was isolated as a mono-HClsalt and the yield was 110 g (82%).

MS: m/z 479, 463, 447, 433, 419, 298, 286, 285, 272, 263, 249, 247, 243,235, 229, 216, 206, 194, 191. ¹H NMR (DMSO-d₆): δ 8.03 (s, 1H); 7.9 (d,1H); 7.35 (d, 1H); 7.1 (m, 2H); 6.9 (m, 2H); 6.7 (m, 1H); 4.6 (m, 2H);4.05 (m, 2H); 3.6 (m, 4H); 3.5 (broad, 6H); 3.3 (s, 3H); 2.5 (m, 2H)

Alternatively, an equivalent amount of compound VIb can be substitutedfor compound VIa to obtain compound IXa.

Step d:

To a mixture of compound IXa (100.0 g, 1.0 eq.) and KHCO₃ (40 g, 1.5eq.) in CH₃CN (500 ml) and water (10 ml) at a temperature between 53 and58° C. was slowly added 2-methoxyphenol cyanate (39.0 g, 1.35 eq.). Thereaction mixture was agitated at a temperature between 53 and 58° C. for1 h. Upon completion of the reaction, a 10% NaOH aqueous solution (200ml) was added to quench the reaction. The batch was then cooled to atemperature between 20 and 25° C., and filtered. The cake was washedwith water (400 ml) and CN₃CN (400 ml) and dried in a vacuum oven at 65to 75° C. for about 12 h. A white product was obtained (ca. 91.0 g) withabout 95% yield.

Mass spectrum: M+1=504. ¹HNMR (DMSO): 8.37 (s, 1H), 8.13 (bs, 2H), 7.95(m, 1H), 7.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55(m, 4H), 2.45 (m, 2H).

Example 2

To a mixture of compound IXa (Example 1, step c) (50.0 g, 1.0 eq.) andDMAP (24.0 g, 2.0 eq.) in CH₃CN (850 ml) at a temperature between 75 and85° C. was slowly added a solution of BrCN (15.0 g, 1.3 eq.) in CH₃CN(150.0 ml). The reaction mixture was refluxed for another 3 h. Thereaction was cooled to 25° C., and 10% NaOH solution (500 ml) was addedto quench the reaction. The batch was filtered, washed with water anddried in a vacuum oven at 65 to 75° C. for about 24 h. A light grayproduct was obtained (ca. 32.0 g).

Mass spectrum: M+1=504. ¹HNMR (DMSO): 8.37 (s, 1H), 8.13 (bs, 2H), 7.95(m, 1H), 7.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55(m, 4H), 2.45 (m, 2H).

Example 3

To a mixture of compound IXa (Example 1, step c) (100.0 g, 1.0 eq.) inTHF (500 ml), water (100 ml) and NaOH (50%, 17.0 g) at a temperaturebetween 60 and 70° C. was slowly added a solution of bisphenol-A cyanate(30.0 g, 1.1 eq.) in THF (125.0 ml). The reaction mixture was refluxedfor another 1.5 h. The reaction mixture was cooled to 25° C., filtered,washed with water and dried in a vacuum oven at 65 to 75° C. for about24 h. A light gray product was obtained (ca. 88.0 g).

Mass spectrum: M+1=504. ¹HNMR (DMSO): 8.37 (s, 1H), 8.13 (bs, 2H), 7.95(m, 1H), 7.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55(m, 4H), 2.45 (m, 2H).

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. The compound of Formula IIIa,